Duke Cancer Institute is participating in a national clinical trial that could reshape the future of CAR T-cell therapy for patients with aggressive lymphoma. Led by industry sponsors and involving multiple institutions, the ALPHA3 trial investigates the potential of allogeneic CAR T-cell treatments to prevent relapse in high-risk patients who appear to be in remission following initial chemotherapy.

Traditional CAR-T therapies use a patient’s own T-cells, known as autologous CAR T-cells, which are genetically modified to target and destroy cancer cells. While effective, this process is complex, time-consuming, and can cause significant side effects due to the intensity of the immune response.

The ALPHA3 trial takes a different approach. Instead of relying on a patient’s own cells, it uses donor-derived allogeneic CAR T-cells. These cells are manufactured in bulk, frozen, and ready for use, offering a faster, potentially less toxic alternative. However, because these cells are foreign to the patient’s body, they are often eliminated by the immune system within weeks, limiting their window of effectiveness.

ALPHA3 is also unique in its focus on patients who are in remission but still at high risk of relapse. After completing chemotherapy, participants undergo a highly sensitive test for measurable residual disease (MRD), a “needle in a haystack” test capable of detecting one cancer cell among millions. If MRD is detected, patients are randomized to receive either allogeneic CAR-T therapy or standard monitoring.

“The hope is that the allogeneic CAR-T will have enough potency to kill off the small number of cancer cells that are hiding in a deep, dark place in the body,” said Mitchell Horwitz, MD, cellular therapy specialist with DCI’s Hematologic Malignancies and Cellular Therapy disease program.

For patients, the trial offers a chance to gain deeper insight into their post-treatment status and potentially receive an intervention that could prevent relapse. From a provider’s perspective, the trial could pave the way for broader use of allogeneic CAR-T therapies.

This multisite trial is highly selective, requiring patients to meet strict criteria for disease risk and MRD positivity.

While early in its implementation, this trial represents a promising evolution in CAR-T therapy.

“These allogeneic CAR-T therapies could be cheaper, quicker to obtain, and less toxic than autologous CAR-T products,” Horwitz said.